The primary objective of the first two years of the K99/R00 award is to provide the candidate with bioinformatics training in the identification and analysis of brain gene expression networks in preparation for an academic research career in the neurophysiological genetics of alcoholism. The candidates specific goal for the K99 phase of the project is to identify gene networks (and key genes regulating these networks) recruited by repeated binge alcohol consumption within brain areas thought to be involved in loss of control over alcohol consumption - the medial Prefrontal Cortex (mPFC) and the ventral Striatum (vSTR; i.e. nucleus accumbens). The candidate will undertake an intensive training regimen to obtain the necessary skills and expertise to analyze and interpret next-generation sequencing data. He will further his career development by completing semester-long didactic coursework in both next-generation sequencing and bioinformatics, and also by attending intensive short courses on the genetics of addiction, statistical genetics, and network analysis. His career development will also be furthered by attending relevant seminars and seminar series offered through the Indiana University Alcohol Research Center (IARC) and Center for Computational Biology and Bioinformatics (CCBB), and by publishing his research findings, attending scientific conferences, and interviewing for independent faculty positions. The proposed mentoring team includes, Drs. Christopher Lapish, Tatiana Foroud, Yunlong Liu, and Howard Edenberg. These individuals collectively are experts in systems and computational electrophysiology, statistical and bioinformatics analyses, and medical/population genomics and genetics. The long-standing collaborative research environment at IUPUI, in particular the IARC, will provide the candidate the necessary resources to complete the aims as outlined in this proposal. At the start of the 3rd year during the R00 phase of the award, the candidate will establish his new role as an independent faculty researcher where he will continue his research on identifying, validating, and characterizing genes and gene networks regulating the brain circuits associated with repeated excessive alcohol consumption, and genetic risk for such consumption. This will be accomplished by combining newly acquired skills in bioinformatics with his current expertise in behavioral physiology and behavioral genetics. Determining the genetic and neurophysiological causes and consequences of excessive alcohol consumption are directly relevant to the mission of the NIAAA in understanding the neurobiology of alcoholism. Specifically, the proposed studies will reveal how the coordinated activity of networks of genes mediates the physiological functioning of a key brain reward circuit to facilitate repeated excessive alcohol consumption. This will result in a better understanding of why and how alcohol use leads to addiction and will help us develop strategies to prevent and treat excessive drinking.